1. Field of the Invention
This invention relates to quinazoline-4-carboxylic acids, processes for preparing them, pharmaceutical compositions containing them and methods of using them as cancer chemotherapeutic agents.
2. Literature Background
Only a small number of 2-aryl-quinazoline-4-carboxylic acids are known. Most have been prepared via a Bischler Synthesis which entails condensation of ammonia with an appropriate N-acylated isatinic acid.
A. Bischler and H. P. Muntendam [Ber., 28. 723 (1895)] and M. T. Bogert and F. P. Nabenhauer [J. Am. Chem. Soc., 46, 1702, (1924)] report 2-aryl-quinazoline-4-carboxylic acids, prepared by the Bischler Synthesis, having the formula: ##STR1## where R=H or CH.sub.3 ; and
R.sup.2 =CH.sub.3, C.sub.2 H.sub.5, C.sub.6 H.sub.5 or C.sub.6 H.sub.4 CO.sub.2 H. PA1 Z can be phenyl or substituted phenyl; and PA1 X and Y are H, halogen, alkyl of 1-3 carbons, alkoxy of 1-3 carbons, nitro, or CF.sub.3. PA1 R.sub.2 is optionally branched carbonyl; PA1 R.sub.4 can be phenyl; and PA1 R.sub.5 is amongst others, alkoxy, dialkylaminoalkoxy, 1-piperidinoalkoxy, and alkylamino. PA1 R.sup.4 is CO.sub.2 H or CO.sub.2 R.sup.11 ; PA1 R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I, CH.sub.3, CF.sub.3, S(O).sub.n R.sup.12 or CH.sub.2 CH.sub.3, at least two of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 being H; PA1 R.sup.9 and R.sup.9A are independently H or alkyl of 1 to 3 carbon atoms; PA1 R.sup.10 is OH, OCH.sub.3, OCH.sub.2 CH.sub.3, NH.sub.2, NHCH.sub.3 or N(CH.sub.3).sub.2 ; PA1 R.sup.11 is (CH.sub.2).sub.2-4 NR.sup.9 R.sup.9A ; PA1 R.sup.12 is alkyl of 1-5 carbon atoms optionally substituted with one or more of F, Cl and Br; PA1 W, Y and Z are independently H, F, Cl, Br, alkyl of 1-5 carbon atoms, NO.sub.2, alkoxy of 1-5 carbon atoms, alkylthio of 1-5 carbon atoms, OH, CF.sub.3 or NH.sub.2 ; PA1 m is 0 or 1; PA1 n is 0 or 1; and PA1 q is 0, 1 or 2; or PA1 (1) R.sup.5, R.sup.6 and R.sup.7 cannot all be H; PA1 (2) when R.sup.4 is CO.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2, R.sup.6 is CH.sub.2 CH.sub.3, or R.sup.7 is Cl, R.sup.1 cannot be cyclohexyl; and PA1 (3) when R.sup.1 is cyclohexyl and R.sup.3 is H, R.sup.6 must be Cl or F, but R.sup.6 and R.sup.8 cannot both be Cl. PA1 R.sup.2 is ##STR14## W and Z are independently H, F, Cl, Br, alkyl of 1-5 carbon atoms, NO.sub.2, alkoxy of 1-5 carbon atoms, OH, CF.sub.3, or NH.sub.2 ; PA1 R.sup.3 is COOH, or COOR.sup.6 ; PA1 R.sup.4 and R.sup.5 are independently H, halogen, CF.sub.3, or alkyl of 1 or 2 carbon atoms; PA1 R.sup.6 is ##STR15## R.sup.7 and R.sup.7a are independently H or alkyl of 1-3 carbon atoms; or a pharmaceutically suitable salt thereof. PA1 (a) R is ##STR16## where W and Z are as defined above; or (b) R.sup.3 is COOH or a salt thereof; or PA1 (c) R.sup.4 and R.sup.5 are independently H or halogen. PA1 (a) 2-(1,1'-Biphenyl-4-yl)-6-fluoro-4-quinazoline carboxylic acid, sodium salt. PA1 (b) 2-(1,1'-Biphenyl-4-yl)-4-quinazoline carboxylic acid, sodium salt.
Meerwein, et al., [Chem. Ber., 89, 224 (1956)] report the synthesis of 2-phenyl-4-quinazoline carboxylic acid from reaction of N-phenylbenzimidoyl chloride and ethylcyanoformate in o-dichlorobenzene containing stannic chloride.
W. Yao, et al. [Yaoxue Xuebao, 19 (1), 76-78 (1984)] report antimalarial quinazoline-4-methanols derived from the corresponding acids including 2-phenyl-4-quinazoline carboxylic acid.
G. G. Glukhovets and B. I. Ardashev [Zh. Khim. 1972, Abstract No. 17Zh309] describe quinazoline analogs of cinchophen of the formula: ##STR2## where R is 4-methyl, 7-methyl or 8-methyl.
R. Pater [J. Heterocycl. Chem., 7(5), 1113-1124, 1970] reports 2-(o-hydroxyphenyl)-4-quinazolinecarboxylic acid, prepared via Bischler's Synthesis as an intermediate to photostable o-hydroxyphenylquinazolines.
M. C. Dubroeucq, et al., in European Patent Appln. No. 112776AZ report 2-(2-chlorophenyl)-4-quinazolinecarboxylic acid which was prepared as an intermediate to the corresponding carboxamide of the formula: ##STR3## where A and B are independently N or CH;
These compounds are useful as anxiolytics, antihypertensives, anti-epileptics and anti-angina agents.
Japanese Patent No. J58172-379-A issued Feb. 4, 1982 describes quinazoline derivatives, which are useful as vasodilators and blood flow improving drugs, of the formula: ##STR4## where R.sub.1 and R.sub.3 are lower alkyl;
Hesson, in copending U.S. patent application Ser. No. 605,104, filed Apr. 4, 1984 describes pharmaceutical compositions, and their method of use as antitumor agents or phenylquinolinecarboxylic acids and derivatives of the formula: ##STR5## wherein R is ##STR6## X is O, S(O).sub.q, NH or CH.dbd.N; R.sup.1 is CH.sub.3 CH.sub.2 (CH.sub.3)CH, alkyl of 5-12 carbon atoms, alkenyl of 5-12 carbon atoms, cycloalkyl of 3-7 carbon atoms, cycloalkylalkyl of 5-12 carbon atoms, cycloalkenyl of 5-7 carbon atoms, ##STR7## when R is ##STR8## R.sup.1 can be in addition alkyl of 3-4 carbon atoms; R.sup.2 is ##STR9## R.sup.3 is H, alkoxy of 1-3 carbon atoms, alkylthio of 1-3 carbon atoms or alkyl of 1-3 carbon atoms optionally substituted with one or more of F, Cl, Br or (CH.sub.2).sub.p COR.sup.10 where p is 1, 2, 3 or 4;
a pharmaceutically suitable salt thereof; with the following provisos: